Skip to main content

Advertisement

SpringerLink
Log in

Constitutive expression of c-REL in uveal melanoma patients: correlation with clinicopathological parameters and patient outcome

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Purpose

Uveal melanoma (UM) is the most common intraocular cancer with a high mortality rate that requires new research in the field of prevention and treatment. c-REL is a member of the nuclear factor κB (NF-κB) transcription factor family and an emerging regulator of tumorigenesis. Therefore, the objective of the study is to evaluate the constitutive expression of c-REL in uveal melanoma patients and its prognostic significance.

Methods

Detection of c-REL expression was carried out by immunohistochemistry in all 75 patients, and qRT-PCR performed on 58 fresh cases of uveal melanoma along with IL-6 status. Immunoblot was performed to validate immunohistochemistry results. Expression of c-REL protein correlated with clinicopathological parameters and overall survival of patients.

Results

Immunohistochemistry results revealed nuclear expression of the c-REL protein (56%) in our cases. Out of 75 cases, 31 cases showed nuclear expression, and 11 cases had cytoplasmic expression. qRT-PCR showed upregulation of the REL gene in 56.89% cases at the transcriptional level. There was a statistically significant difference in the overall survival of patients with c-REL nuclear immunopositivity (p = 0.0048). On multivariate analysis, scleral invasion and c-REL nuclear expression found to be an independent prognostic factor (p < 0.05)

Conclusions

To the best of our knowledge, this was the first study reporting the expression of the c-REL protein in uveal melanoma. Strong nuclear immunoexpression of c-Rel suggests NFκB pathway activation which might be involved in the progression of the disease. Differential expression of c-REL protein may be used as an attractive target for the development of anticancer strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Amaro A, Gangemi R, Piaggio F, et al. The biology of uveal melanoma. Cancer Metastasis Rev. 2017;36:109–40.

    Article  Google Scholar 

  2. Nathan P, Cohen V, Coupland S, et al. United Kingdom Uveal Melanoma Guideline Development Working Group. Eur J Cancer. 2015;51:2404–12.

    Article  CAS  Google Scholar 

  3. Diener-West M, Reynolds SM, Agugliaro DJ, et al. Collaborative Ocular Melanoma Study Group Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: collaborative ocular melanoma study group report no. 26. Arch Ophthalmol. 2005;123: 1639–1643.

  4. Rietschel P, Panageas KS, Hanlon C, et al. Variates of survival in metastatic uveal melanoma. J Clin Oncol. 2005;23:7576.

    Article  Google Scholar 

  5. Damato B. Does ocular treatment of uveal melanoma influence survival? Br J Cancer. 2010;103:285–90.

    Article  CAS  Google Scholar 

  6. Li Q, Verma IM. NF-κB regulation in the immune system. Nat Rev Immunol. 2002;2:725–34.

    Article  CAS  Google Scholar 

  7. Karin M, Cao Y, Greten FR, Li ZW. NF-kB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002;2:301–10.

    Article  CAS  Google Scholar 

  8. Ben-Neriah Y, Karin M. Inflammation meets cancer, with NFkappaB as the matchmaker. Nat Immunol. 2011;12:715–23.

    Article  CAS  Google Scholar 

  9. Grivennikov SI, Karin M. Dangerous liaisons: STAT3 and NF kappa B collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 2010;21:11–9.

    Article  CAS  Google Scholar 

  10. Gilmore TD, Gerondakis S. The c-REL transcription factor in development and disease. Genes Cancer. 2011;2:695–711.

    Article  CAS  Google Scholar 

  11. Wang Y, Rickman BH, Poutahidis T, et al. c-REL is essential for the development of innate and T cell-induced colitis. J Immunol. 2008;175:8118–255.

    Article  Google Scholar 

  12. Compagno M, Lim WK, Grunn A, et al. Mutations of multiple genes cause deregulation of NF-kB in diffuse large B-cell lymphoma. Nature. 2009;459:717–21.

    Article  CAS  Google Scholar 

  13. Hamoudi RA, Appert A, Ye H, et al. Differential expression of NF-kB target genes in MALT lymphoma with and without chromosome translocation: insights into molecular mechanism. Leukemia. 2010;24:1487–97.

    Article  CAS  Google Scholar 

  14. Geismann C, Grohmann F, Sebens S, et al. c-REL is a critical mediator of NF-kB dependent TRAIL resistance of pancreatic cancer cells. Cell Death Dis. 2014;5:e1455.

    Article  CAS  Google Scholar 

  15. Cogswell PC, Guttridge DC, Funkhouser WK, Baldwin AS Jr. Selective activation of NF-kB subunits in human breast cancer: potential roles for NF-kB2/p52 and for Bcl-3. Oncogene. 2000;19:1123–31.

    Article  CAS  Google Scholar 

  16. Gieling RG, Elsharkawy AM, Caamano JH, et al. The c-REL subunit of nuclear factor-kB regulates murine liver inflammation, wound-healing, and hepatocyte proliferation. Hepatology. 2010;51:922–31.

    Article  CAS  Google Scholar 

  17. Elsharkawy AM, Mann DA. Nuclear factor-kB and the hepatic inflammation-fibrosis-cancer axis. Hepatology. 2007;46:590–7.

    Article  CAS  Google Scholar 

  18. McNulty SE, del Rosario R, Cen D, Meyskens FL Jr, Yang S. Comparative expression of NFkappa B proteins in melanocytes of normal skin vs. benign intradermal naevus and human metastatic melanoma biopsies. Pigment Cell Res. 2004;17:173–180.

    Article  CAS  Google Scholar 

  19. Wang Y, Rickman BH, Poutahidis T, et al. c-REL is essential for the development of innate and T cell-induced colitis. J Immunol. 2008;180:8118–255.

    Article  CAS  Google Scholar 

  20. Gilmore TD, Gerondakis S. The c-REL transcription factor in development and disease. Genes Cancer. 2011;2:695–711.

    Article  CAS  Google Scholar 

  21. Lu YC, Kim I, Lye E, Shen F, Suzuki N, Suzuki S, Gerondakis S, Akira S, Gaffen SL, Yeh WC, Ohashi PS. Differential role for c-Rel and C/EBPbeta/delta in TLR-mediated induction of proinflammatory cytokines. J Immunol. 2009;182:7212–21.

    Article  CAS  Google Scholar 

  22. Dror R, Lederman M, Umezawa K, Barak V, Pe'er J, Chowers I. Characterizing the involvement of the nuclear factor-kappa B (NFκB) transcription factor in uveal melanoma. Invest Ophthalmol Vis Sci. 2010;51:1811–6.

    Article  Google Scholar 

  23. Liu N, Sun Q, Chen J, Li J, Zeng Y, Zhai S, Li P, Wang B, Wang X. MicroRNA-9 suppresses uveal melanoma cell migration and invasion through the NF-κB1 pathway. Oncol Rep. 2012;28:961–8.

    PubMed  Google Scholar 

  24. Makitie T, Summanen P, Tarkkanen A, Kivelä T. Tumor-infiltrating macrophages (CD68(+) cells) and prognosis in malignant uveal melanoma. Invest Ophthalmol Vis Sci. 2001;42(7):1414–21.

    CAS  PubMed  Google Scholar 

  25. McLean IW, Foster WD, Zimmerman LE, Gamel JW. Modifications of Callender’s classification of uveal melanoma at the Armed Forces Institute of Pathology. Am J Ophthalmol. 1983;96:502–9.

    Article  CAS  Google Scholar 

  26. The AJCC Ophthalmic Oncology Task Force. International Validation of the American Joint Committee on Cancer’s 7th Edition Classification of Uveal Melanoma. JAMA Ophthalmol. 2015; 133: 376–383.

    Article  Google Scholar 

  27. Li Z, Han C, Feng J. Relationship of the expression levels of XIAP and p53 genes in hepatocellular carcinoma and the prognosis of patients. Oncol Lett. 2017;14(4):4037–42.

    Article  Google Scholar 

  28. Rodig SJ, Savage KJ, LaCasce AS, et al. Expression of TRAF1 and nuclear c-REL distinguishes primary mediastinal large cell lymphoma from other types of diffuse large B-cell lymphoma. Am J Surg Pathol. 2007;31:106–12.

    Article  Google Scholar 

  29. Tarlan B, Kıratlı H. Uveal melanoma: current trends in diagnosis and management. Turk J Ophthalmol. 2016;46:123–37.

    Article  Google Scholar 

  30. Shields CL, Shields JA, Kiratli H, De Potter P, Cater JR. Risk factors for growth and metastasis of small choroidal melanocytic lesions. Ophthalmology. 1995;102:1351–61.

    Article  CAS  Google Scholar 

  31. Shields CL, Furuta M, Thangappan A, et al. Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol. 2009;127:989–98.

    Article  Google Scholar 

  32. Diener-West M, Reynolds SM, Agugliaro DJ, et al. Collaborative Ocular Melanoma Study Group Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: collaborative ocular melanoma study group report no. 26. Arch Ophthalmol. 2005; 123: 1639–1643.

  33. Singh AD, Shields CL, Shields JA. Prognostic factors in uveal melanoma. Melanoma Res. 2001;11:255–63.

    Article  CAS  Google Scholar 

  34. Jager MJ, Ly LV, El Filali M, et al. Macrophages in uveal melanoma and in experimental ocular tumor models: Friends or foes? Prog Retin Eye Res. 2011;30:129–46.

    Article  CAS  Google Scholar 

  35. Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017; 2:17023.

  36. Terai M, Mastrangleo MJ, Sato T. Immunological aspect of the liver and metastatic uveal melanoma. J Cancer Metastasis Treat. 2017;3:231–43.

    Article  CAS  Google Scholar 

  37. Weniger MA, Gesk S, Ehrlich S, et al. Gains of REL in primary mediastinal B-cell lymphoma coincide with nuclear accumulation of REL protein. Gene Chromosome Cancer. 2007;46:406–15.

    Article  CAS  Google Scholar 

  38. Li L, Xu-Monette ZY, Ok CY, Tzankov A, Manyam GC, Sun R, Visco C, Zhang M, et al. Prognostic impact of c-REL nuclear expression and REL amplification and crosstalk between c-REL and the p53 pathway in diffuse large B-cell lymphoma. Oncotarget. 2015;15:23517–80.

    Google Scholar 

  39. Barth TF, Martin-Subero JI, Joos S, et al. Gains of 2p involving the REL locus correlate with nuclear c-REL protein accumulation in neoplastic cells of classical Hodgkin lymphoma. Blood. 2003;101:3681–6.

    Article  CAS  Google Scholar 

  40. Curry CV, Ewton AA, Olsen RJ, et al. Prognostic impact of c-REL expression in diffuse large B-cell lymphoma. J Hematop. 2009;2:20–6.

    Article  Google Scholar 

Download references

Acknowledgements

Mithalesh Kumar Singh was thankful to Indian Council of Medical Research for providing Senior Research Fellowship (SRF). We are grateful to Mr. Pankaj Kumar for providing technical support in IHC.

Author information

Authors and Affiliations

  1. Department of Ocular Pathology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India

    M. K. Singh, S. Sen & S. Kashyap

  2. Departrment of Biosciences, JMI, New Delhi, India

    L. Singh

  3. Department of Ophthalmology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India

    N. Pushker & R. Meel

  4. Department of Biochemistry, AIIMS, New Delhi, India

    K. Chosdol

  5. Department of Medical Oncology, IRCH, AIIMS, New Delhi, India

    S. Bakhshi

Authors
  1. M. K. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. Pushker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K. Chosdol
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Bakhshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R. Meel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S. Sen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S. Kashyap
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MKS and SK are responsible for the conception or design of the work. MKS, LS and KC contribute the acquisition, analysis, or interpretation of data for the work. NP, and RM provide the tissue samples. SB helps in the follow-up of the patients. SS helps in reviewing the histopathology slides. All authors finally approved the manuscript version to be published. SK is the guarantor of the article.

Corresponding author

Correspondence to S. Kashyap.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by Institutional Ethical Committee, All India Institute of Medical Sciences, New Delhi, India and conducted in accordance with the ethical standards.

Informerd consent

Yes.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (Tif 91461 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Singh, M.K., Singh, L., Pushker, N. et al. Constitutive expression of c-REL in uveal melanoma patients: correlation with clinicopathological parameters and patient outcome. Clin Transl Oncol 22, 1193–1204 (2020). https://doi.org/10.1007/s12094-019-02247-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-019-02247-z

Keywords

Search

Navigation